Mesenchymal lineage precursor or stem cells with enhanced immunosuppression

a mesenchymal lineage and immunosuppression technology, applied in the direction of drug compositions, skeletal/connective tissue cells, biochemistry apparatus and processes, etc., can solve the problems of inability to confirm the biological activity and potency of a product by physiochemical parameters, and difficult to define consistent cellular therapy product quality, etc., to achieve the effect of improving immunosuppressive activity

Pending Publication Date: 2020-10-15
MESOBLAST INT
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0011]The Applicant has developed an off-the-shelf ex vivo expanded allogeneic mesenchymal lineage precursor or stem cell (MLPSC) product which has improved immunosuppressive activity.

Problems solved by technology

However, release of these cellular therapy products onto the market is hindered by their complexity and heterogeneity, which makes identification of relevant biologic activities and thus, definition of consistent cellular therapy product quality difficult.
However, physiochemical parameters cannot confirm that a product will be biologically active and potent (i.e., elicit the desired effect).

Method used

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  • Mesenchymal lineage precursor or stem cells with enhanced immunosuppression
  • Mesenchymal lineage precursor or stem cells with enhanced immunosuppression
  • Mesenchymal lineage precursor or stem cells with enhanced immunosuppression

Examples

Experimental program
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example 1

Materials and Methods

Mesenchymal Lineage Precursor or Stem Cells (MLPSCs) Prepared Using Plastic Adherence Techniques

[0353]MLPSCs were generated de novo from bone marrow as described in U.S. Pat. No. 5,837,539. Approximately 80-100 ml of bone marrow was aspirated into sterile heparin-containing syringes and taken to the MDACC Cell Therapy Laboratory for MSC generation. The bone marrow mononuclear cells were isolated using ficoll-hypaque and placed into two T175 flask with 50 ml per flask of MLPSC expansion medium which includes alpha modified MEM (αMEM) containing gentamycin, glutamine (2 mM) and 20% (v / v) fetal bovine serum (FBS) (Hyclone).

The cells were cultured for 2-3 days in 37° C., 5% CO2 at which time the non-adherent cells were removed; the remaining adherent cells were continually cultured until the cell confluence reached 70% or higher (7-10 days), and then the cells were trypsinized and replaced in six T175 flasks with expansion medium (50 ml of medium per flask).

Immunose...

example 2

ected Mesenchymal Lineage Precursor or Stem Cells with Enhanced Immunosuppressive Properties

[0386]The immunosuppressive potential of immunoselected mesenchymal lineage precursor or stem cells (MLPSCs) were assess by comparison with products obtained by the previous manufacturing process (as described in U.S. Pat. No. 9,828,586). Results of the T cell proliferation assay (% inhibition of IL2R) performed on three different samples of MLPSCs produced under the previous manufacturing conditions (i.e. samples MLPSC A, MLPSC B and MLPSC C) and three different samples of improved immunoselected MLPSCs with (i.e. samples MLPSC D, MLPSC E and MLPSC F) compared to are shown in FIG. 2. These results show that the assay differentiates between a first class of multipotential lineage cells and a second class of multipotential lineage cells in terms of ability to inhibit T-cell proliferation. In particular, the second class of cells inhibits T cell proliferation substantially more effectively that...

example 3

: Mesenchymal Lineage Precursor or Stem Cell (MLPSC) with Low IL-2R Inhibition Infused for the Treatment of Pediatric Subjects Who are Steroid Refractory

[0389]This study is for the treatment of pediatric patients who have failed to respond to steroid treatment for acute graft-versus-host disease (GVHD). Failing steroid treatment for acute GVHD is defined as any Grade B-D (IBMTR grading) of acute GVHD that is not improving after at least 3 days of methylprednisolone≥1 mg / kg / day) or equivalent.

[0390]Patients were treated with ex-vivo cultured MLPSC with low IL-2R inhibition twice per week at a dose of 2×106 hMSC / kg (actual body weight) for each of 4 consecutive weeks. Infusions were administered at least 3 days apart.

[0391]Study Design:

[0392]241 pediatric patients undergoing HSCT were enrolled and treated at 50 sites in North America and Europe from 2007-2014

[0393]Ages 2 months-17 years

[0394]Acute GvHD grades B-D (CIBMTR)

[0395]Failed steroid treatment and multiple other agents

[0396]aG...

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Abstract

The present disclosure relates to cellular therapy products comprising mesenchymal lineage precursor or stem cells and potency assay for these products. The present disclosure also relates to methods for treatment of immune or inflammatory disorders, and treatment or prevention of graft versus host disease (GVHD), or one or more symptoms associated with GVHD, by administration of mesenchymal lineage precursor or stem cells.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a § 371 national stage of PCT International Application No. PCT / EP2018 / 061503, filed May 4, 2018, claiming priority of Australian Provisional Application No. AU 2018900551, filed Feb. 21, 2018; Australian Provisional Application No. AU 2017901636, filed May 4, 2017; and Australian Provisional Application No. AU 2017901633, filed May 4, 2017, the contents of each of which are hereby incorporated by reference into the application.[0002]All documents cited or referenced herein, and all documents cited or referenced in herein cited documents, together with any manufacturer's instructions, descriptions, product specifications, and product sheets for any products mentioned herein or in any document incorporated by reference herein, are hereby incorporated herein by reference in their entirety.[0003]All documents cited or referenced herein, and all documents cited or referenced in herein cited documents, together with any man...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C12N5/0775A61P29/00
CPCC12N2502/1157C12N5/0663C12N2523/00A61P29/00A61K35/28C12N5/0662
Inventor ITESCU, SILVIUSIMMONS, PAUL
Owner MESOBLAST INT
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